PROJECT SUMMARY Our work and that of others has established that older people with lower extremity peripheral artery disease (PAD) have greater functional impairment, faster functional decline, and increased rates of mobility loss compared to people without PAD. However, few effective medical therapies have been identified for improving lower extremity functioning or preventing functional decline in people with PAD. VM202 is a plasmid that contains cDNA and encodes two isoforms of hepatocyte growth factor (HGF). VM202 is administered by intra-muscular injection into calf muscle where it locally produces HGF. HGF is a paracrine cellular growth factor that stimulates angiogenesis, promotes skeletal muscle regeneration, and improves autophagy. Preliminary evidence in PAD patients with critical limb ischemia (CLI) showed that HGF improved the ankle brachial index (ABI), a measure of PAD severity, and promoted lower extremity ulcer healing. We hypothesize that the favorable effects of HGF will improve walking performance in PAD patients without CLI. We propose a pilot double blinded randomized clinical trial to provide preliminary data to address our hypothesis that VM202 therapy, injected into calf skeletal muscle bilaterally, improves lower extremity functioning in older people with PAD, by increasing angiogenesis, improving calf muscle perfusion, and promoting calf skeletal muscle regeneration. Participants will be 36 people with PAD age 65 and older who do not have CLI. In our primary aim, we will determine whether PAD participants randomized to calf skeletal muscle injections of VM202 have greater increases or smaller declines in six-minute walk performance at 3-month follow-up, compared to those randomized to calf skeletal muscle injections of placebo. In our secondary aims, we will determine whether PAD participants randomized to VM202 have greater improvements in treadmill walking performance, calf skeletal muscle perfusion, and calf muscle biopsy measures of capillary density, skeletal muscle regeneration, and autophagy, compared to placebo. If our hypotheses are correct, results will be used to design a large, definitive randomized clinical trial of VM202 to improve lower extremity functioning and prevent mobility loss in the large and growing number of older people who are disabled by PAD and do not have CLI.